In Drosophila, asymmetric division by neural precursor cells, a process by which two different daughter cells are generated, plays important roles during nervous system development. The numb gene plays a central role in such asymmetric divisions. numb encodes a membrane-associated protein that becomes asymmetrically localized to only one half of the cell membrane in dividing neural precursor cells necessary for the daughter cells to adopt distinct fates. While mammalian neural progenitor cells are capable of dividing asymmetrically, the precise roles that asymmetric division plays, and what its molecular mechanism is, remain largely unknown. We are studying two mammalian homologues of numb, m-numb and numblike. Based on preliminary studies, we have postulated that, as in Drosophila, asymmetric segregation of m-Numb protein to only one daughter cell provides a cell-intrinsic mechanism that allows neural progenitor cells to divide asymmetrically. Our long term goal is to use m-numb and numblike as an entry point to pinpoint the precise roles that asymmetric cell division plays in mammalian neurogenesis. Towards this end, we have generated conditional m-numb mutant mice as well as numblike mutant mice. We intend to use both in vivo and in vitro approaches to characterize the defects in m-numb and numblike mutant mice by focusing on three types of neural cell fate choices (neuron vs. progenitor, neuron vs. glia, and between different neuronal subtypes). We will further examine whether such defects result from the inability of mutant neural progenitor cells to divide asymmetrically. The application lists four specific aims, the success of which may elucidate the roles that cell-intrinsic mechanisms play in mammalian neural development. Understanding how neural progenitor cells divide asymmetrically may help us to better understand how stem cells are maintained and how diverse neurons are generated during development. Such knowledge can point to mechanisms that cause brain cells to revert to less differentiated states in brain tumors or to degenerate in neurological disorders.